Body weight is determined by the balance between energy input and expenditure. Skeletal muscle is major site of mitochondrial oxidative metabolism of fatty acids and glucose and thereby plays a central role in whole body energy expenditure. Accordingly, preservation or promotion of skeletal muscle metabolism could play a critical role in protection from diet induced obesity. Understanding the mechanisms that regulate skeletal muscle metabolism and their relationship to those controlling fatty storage and mobilization is therefore a critical goal in metabolic disease research. Lipin1 is a phosphatidic acid (PA) phosphatase enzyme that catalyzes the penultimate step in triglyceride synthesis at the cytoplasmic surface of the endoplasmic reticulum and also serves as a nuclear transcriptional co-activator of PPAR-? responsive genes. Lipin1 deficient mice (fatty liver dystrophy mice, fid mice) exhibit impaired adipocyte differentiation, circulating hyperlipidemia and neonatal hepatic steatosis associated with diminished rates of hepatic fatty acid oxidation. Lipin1 is also expressed in skeletal muscle and transgenic overexpression of lipin1 in this tissue reverses many of the phenotypes of lipin1 deficient fid mice. Interestingly, humans with heritable lipin1 null mutations present with severe rhabdomyolysis (skeletal, muscle degeneration) characterized by impaired carnitine palmitoyi acyltransferase (CPT) activity, decreased mitochondrial fatty oxidation and respiratory chain function and the consequent destruction of skeletal muscle fibers. We made the seminal observation that lipin1 is recruited to the mitochondrial surface where it promotes mitochondrial fission and remodels mitochondrial lipids, suggesting that lipin1 deficiency impacts directly on mitochondrial function. Based on these observations we propose that lipin1 is poised to function as a link between fatty acid and carbohydrate metabolism in muscle and fat. Accordingly, we hypothesize that recruitment of lipin1 to mitochondria directly promotes mitochondrial respiratory function and beta-oxidation through effects on mitochondrial homeostasis and lipid composition and that this is particularly important for skeletal muscle function in energy metabolism. In direct support of our hypothesis, we found mitochondrial respiratory function is impaired in lipin1 deficient mouse embryo fibroblasts and mitochondria isolated from skeletal muscle of lipin1 deficient mice. The broad goal of this research is to define the role of Lipin1 in mitochondrial function and skeletal muscle physiology. Aim 1 defines the role of muscle cell lipin1 PA phosphatase activity in regulating mitochondrial lipid composition and function, while Aim 2 examines deletion of skeletal muscle lipin1 in lean and obese mice.